Objective ·To investigate the causal relationship between atrial fibrillation (AF) and cognitive impairment. Methods ·A two-sample Mendelian randomization (TSMR) analysis was used to assess the potential causality of AF on cognitive dysfunction. Single nucleotide polymorphisms (SNPs) strongly associated with AF were extracted as instrumental variables by using a dataset of a large-scale genome-wide association study (GWAS) on AF. The associations of SNPs with Alzheimer′s disease dementia, Parkinson′s disease dementia, vascular dementia, Lewy body dementia, frontotemporal dementia, undefined dementia, and overall cognitive function assessment were extracted separately from publicly available GWAS data on cognitive dysfunction. The inverse variance-weighted (IVW) method was used for the main analysis, and sensitivity analyses were conducted by using Cochran′s Q test, MR-Egger regression, and leave-one-out method. To verify the robustness of the results, replicate analyses and meta-analyses were performed by using different GWAS data. Results ·In the initial analysis, 101 SNPs were extracted as instrumental variables from a meta-analysis of a genome-wide association study involving up to 1 030 836 individuals. The IVW analysis showed no evidence for causal associations between AF and dementia [dementia (OR=1.032; 95%CI 0.973?1.094; P=0.290), Parkinson′s disease dementia (OR=1.004; 95%CI 0.780?1.291; P=0.977), vascular dementia (OR=1.123; 95%CI 0.969?1.301; P=0.125), or unspecified dementia (OR=1.013; 95%CI 0.910?1.129; P=0.807)]. In the replication analysis, 27 SNPs were extracted as instrumental variables from the FinnGen AF GWAS data, and the IVW analysis were consistent with the initial analysis [cognitive function (OR=0.999; 95%CI 0.982?1.016; P=0.874), Alzheimer′s disease dementia (OR=0.977; 95%CI 0.943?1.012; P=0.193), Lewy body dementia (OR=1.014; 95%CI 0.898?1.145; P=0.826), or frontotemporal dementia (OR=0.996; 95%CI 0.745?1.333; P=0.980)]. Both Mendelian randomization analyses and meta-analyses showed no evidence of an association between genetically predicted AF and different types of dementia or overall cognitive function assessment. MR-Egger regression suggested no horizontal pleiotropy and leave-one-out analysis showed stable results after individually removing each SNP. Conclusion ·No evidence of a causal relationship between AF and cognitive impairment was found. The associations observed in observational studies can be partially attributed to confounding factors such as shared biology or co-morbidities.